Delivery of a therapeutic agent from an implantable medical device can be desirable for a variety of applications. Therapeutic agents can be released from a medical device, such as an expandable stent or valve, to treat or mitigate undesirable conditions including restenosis, tumor formation or thrombosis. Procedures for mitigating certain conditions can include implantation of a device comprising a therapeutic agent. For example, the implantation of stents during angioplasty procedures has substantially advanced the treatment of occluded body vessels. Angioplasty procedures such as Percutaneous Transluminal Coronary Angioplasty (PCTA) can widen a narrowing or occlusion of a blood vessel by dilation with a balloon.
Occasionally, angioplasty may be followed by an abrupt closure of the vessel or by a more gradual closure of the vessel, commonly known as restenosis. Restenosis refers to the renarrowing of the vascular lumen following vascular intervention, such as coronary artery balloon angioplasty with or without stent insertion. Restenosis is clinically defined as greater than 50% loss of initial luminal diameter gain following the procedure. Restenosis is believed to occur in about 30% to 60% of lesions treated by angioplasty and about 20% of lesions treated with stents within 3 to 6 months following the procedure. Acute closure may result from an elastic rebound of the vessel wall and/or by the deposition of blood platelets and fibrin along a damaged length of the newly opened blood vessel. In addition, restenosis may result from the natural healing reaction to the injury to the vessel wall (known as intimal hyperplasia), which can involve the migration and proliferation of medial smooth muscle cells that continues until the vessel is again occluded. To prevent such vessel occlusion, stents have been implanted within a body vessel. However, restenosis may still occur over the length of the stent and/or past the ends of the stent where the inward forces of the stenosis are unopposed.
To reduce the incidence of restenosis, one or more therapeutic agents, such as paclitaxel or other anti-restenotic agents, may be coated on the medical device. Paclitaxel is a compound which disrupts mitosis (M-phase) by binding to tubulin to form abnormal mitotic spindles or an analogue or derivative thereof. Such medical device coatings may be configured in various ways to release a therapeutic agent at a desired rate and over a desired time period upon implantation. Preferably, an implanted medical device releases a therapeutic agent at a point of treatment within a body vessel to promote a therapeutically desirable outcome, such as mitigation of restenosis.
For example, some medical device coatings include multi-layer coatings with separate layers having different-sized particles comprising the therapeutic agent. Published U.S. patent application US 2002/0082680 A1 by Shanley et al., filed Sep. 7, 2001, describes an expandable medical device having multiple layers comprising a beneficial agent stacked within an opening in a strut. Each layer may include particles of different sizes comprising the beneficial agent with differences in the particle sizes from layer to layer being selected to adjust the total drug flux eluting from the device as a function of the different particle sizes in each layer. Published U.S. patent application US 2005/0095267 A1 by Campbell et al., filed Dec. 3, 2003, describe implantable medical devices having nanoparticle drug coatings to improve the solubility of the drug. U.S. Pat. No. 5,873,313 to Ding et al., filed Jun. 13, 1996, describes spray coating of medical devices with microparticles of heparin using a pressurized airbrush.
Other medical device coatings adapted for controlled release of therapeutic agents such as paclitaxel rely on a polymer coating that is mixed with or applied over the releasable therapeutic agent to slow the release of the therapeutic agent from the medical device surface. For example, U.S. Pat. No. 6,589,546 to Kamath et al (filed Dec. 10, 2001) and Published US Patent Application 2004/0039441 by Rowland et al. (filed May 20, 2003) describe medical device coatings comprising a therapeutic agent mixed with a polymer to provide a controlled release of the therapeutic agent. Published US Patent Application 2003/0236513 by Schwarz et al. (filed Jun. 19, 2002) described medical device coatings comprising a polymer coating deposited over or mixed with a therapeutic agent to control the rate of release of the therapeutic agent from the device. U.S. Pat. No. 6,663,662 to Pacetti et al., filed Dec. 28, 2000, describes a multilayer medical device coating including a polymer diffusion barrier coating layer for reducing the elution rate of an underlying therapeutic substance. U.S. Pat. No. 6,770,729 to Van Antwerp, filed Sep. 30, 2002, discloses a medical device coating comprising a polymer mixed with a bioactive material to provide a controlled release of the bioactive material from the coating layer.
Typically, medical device coatings are configured to release a therapeutic agent at the same rate from all portions of the coating. However, for some clinical indications, adverse clinical indications, such as restenosis, may occur at only certain portions of the medical device surface. A therapeutic agent eluting device, such as a coated coronary stent, is typically selected to have a length at least equal to a length of an injured site (e.g., lesion) so as to extend the entire length of a lesion, preferably extending beyond the lesion. In some instances, restenosis may occur in tissue at or near the edges of the stent. This narrowing of the artery just beyond the edges of the stent is called the “edge effect.” In patients experiencing the edge effect, a stented portion of a body vessel may remain free of significant restenosis, but portions of the body vessel at or beyond the edges of the stent may develop significant or even severe restenosis, requiring subsequent treatment. The seventy of the restenosis at the edge and/or beyond edge areas is often greater at a portion of a body vessel proximal to the stent. The occurrence of edge effect may be attributable to uncovered diseased segments subjected to balloon trauma that are not covered by the stent, migration of smooth cells from the lesioned area, injury during the interventional procedure (e.g., balloon injury during angioplasty with or without the stenting), or the insufficient coverage of the original lesion. In the case of drug eluting stents, such effect may further be attributable to drastic gradient change between areas directly exposed to the drug and areas not directly exposed to the drug.
What is needed are medical devices that permit release of a therapeutic agent at a greater rate and/or a longer period of time from portions of the medical device coating that are prone to the edge effect. In particular, medical device coatings are needed that are capable of eluting a therapeutic agent at a different rate in at least two different regions of the abluminal surface of the device, with or without a polymer.